Dose selection for rifabutin in combination with HIV-protease inhibitors

 

Aims: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV-protease inhibitors, and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated tuberculosis, with concurrently administered protease inhibitors.

 

Methods: Individual level data from 13 published studies were pooled, and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin), and drug-drug interaction with protease inhibitors in healthy volunteers and patients who had HIV and tuberculosis (TB/HIV). Repeatedly significant covariates were tested collectively using a linearized stepwise covariate model (lin-SCM) building method implemented in the software PsN to reduce runtime and enable an extensive search for possible relations.(1) Final estimated model parameters were used to calculate the expected average steady-state concentrations (Cav_ss) for rifabutin and steady state peak concentration (Cmax_ss) for rifabutin and des-rifabutin were predicted from the final model using Berkeley Madonna software to identify dosing regimens that provided an exposure >0.187 mg/L (Cav_ss) (2, 3), which previously was associated with acquired rifamycin resistance and dose-related toxicity (4, 5), respectively.

 

Results: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation to the metabolite (increased by 224% in patients), volume of distribution (increased by 606%), and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, the clearance was reduced by 35% to 76% and volume of distribution increased by 67% to 240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of protease inhibitors and 280% with ritonavir-boosted protease inhibitors.

 

Conclusion: Given together with nonboosted or ritonavir-boosted protease inhibitors, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant protease inhibitors, and may achieve peak concentrations within acceptable therapeutic range. Although 300 mg rifabutin every three days with boosted protease inhibitor achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.

 

References:

 

1.  Khandelwal A, Harling K, Jonsson EN, et al. A fast method for testing covariates in population PK/PD Models. AAPS J. 2011;13:464-72.

 

2.  Weiner M, Benator D, Peloquin CA, et al. Evaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis. Clin Infect Dis. 2005;41:1343-9.

 

3.  Weiner M, Benator D, Burman W, et al. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis. Clin Infect Dis. 2005;40(10):1481-91.

 

4.  McGregor MM, Olliaro P, Wolmarans L, et al. Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Am J Respir Crit Care Med. 1996;154(5):1462-7.

 

5.  Gonzalez-Montaner LJ, Natal S, Yongchaiyud P, et al. Rifabutin for the treatment of newly-diagnosed pulmonary tuberculosis: a multinational, randomized, comparative study versus Rifampicin. Rifabutin Study Group. Tuber Lung Dis. 1994;75(5):341-7.